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NVP-BEZ235 overcomes gefitinib-acquired resistance by down-regulating PI3K/AKT/mTOR phosphorylation.

Sun Z, Li Q, Zhang S, Chen J, Huang L, Ren J, Chang Y, Liang Y, Wu G - Onco Targets Ther (2015)

Bottom Line: We show that NVP-BEZ235 effectively inhibited the growth of H1975 cells in vivo as well as in vitro.Similarly, H1975 cell migration was reduced by NVP-BEZ235.Taken together, we suggest that NVP-BEZ235 inhibits gefitinib-resistant tumor growth by downregulating PI3K/AKT/mTOR phosphorylation.

View Article: PubMed Central - PubMed

Affiliation: Oncology department, Xiangyang central Hospital, Xiangyang, Hubei, People's Republic of China.

ABSTRACT

Background: Patients harboring activating mutations in epidermal growth factor receptors (EGFR) are particularly sensitive to EGFR tyrosine kinase inhibitors (TKIs). However, most patients develop an acquired resistance after a period of about 10 months. This study focuses on the therapeutic effect of NVP-BEZ235, a dual inhibitor of phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR), in gefitinib-resistant non-small cell lung cancer.

Methods: H1975 cell line was validated as a gefitinib-resistant cell model by the nucleotide-sequence analysis. We used the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to detect the growth of H1975 cell line in vitro. H1975 cells' migration was detected by the migration assay. Xenograft models were used to investigate the growth of gefitinib-resistant non-small cell lung cancer in vivo. Western blot and immunohistochemical analysis were used to investigate the level of PI3K/protein kinase B(AKT)/mTOR signaling pathway proteins.

Results: We show that NVP-BEZ235 effectively inhibited the growth of H1975 cells in vivo as well as in vitro. Similarly, H1975 cell migration was reduced by NVP-BEZ235. Further experiments revealed that NVP-BEZ235 attenuated the phosphorylation of PI3K/AKT/mTOR signaling pathway proteins.

Conclusion: Taken together, we suggest that NVP-BEZ235 inhibits gefitinib-resistant tumor growth by downregulating PI3K/AKT/mTOR phosphorylation.

No MeSH data available.


Related in: MedlinePlus

H1975 cells were implanted into nude mice. (A) The tumor volume did not show significant difference, before treatment with different components. (B) The tumor volumes started to show differences with different components’ treatment. (C) The observation of tumors after 2 weeks of different components’ treatment.Abbreviations: B+G, NVP-BEZ235 combination with gefitinib; BEZ, NVP-BEZ235; BLK, blank control; GEF, gefitinib.
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f3-ott-8-269: H1975 cells were implanted into nude mice. (A) The tumor volume did not show significant difference, before treatment with different components. (B) The tumor volumes started to show differences with different components’ treatment. (C) The observation of tumors after 2 weeks of different components’ treatment.Abbreviations: B+G, NVP-BEZ235 combination with gefitinib; BEZ, NVP-BEZ235; BLK, blank control; GEF, gefitinib.

Mentions: In view of the in vitro growth-inhibiting effects of BEZ235 on H1975 cells, we verified its in vivo inhibitory action in nude mice. The mice were randomized into four groups with similar average tumor volume (Figure 3A). As expected, the tumor volume was decreased two weeks after BEZ235 administration. At the end of treatment, the average tumor volume of the blank group was 1973.22±156.04 mm3, while the average tumor volume of BEZ235 group was 1198.76±123.28 mm3 and 379.92±54.74 mm3 for the combination group, respectively. The tumor volumes of BEZ235 alone and the combination groups were significantly different from that of the blank group (P<0.05). These in vivo findings further demonstrated that BEZ235 significantly inhibited the growth of H1975 xenografts (Figure 3B and C).


NVP-BEZ235 overcomes gefitinib-acquired resistance by down-regulating PI3K/AKT/mTOR phosphorylation.

Sun Z, Li Q, Zhang S, Chen J, Huang L, Ren J, Chang Y, Liang Y, Wu G - Onco Targets Ther (2015)

H1975 cells were implanted into nude mice. (A) The tumor volume did not show significant difference, before treatment with different components. (B) The tumor volumes started to show differences with different components’ treatment. (C) The observation of tumors after 2 weeks of different components’ treatment.Abbreviations: B+G, NVP-BEZ235 combination with gefitinib; BEZ, NVP-BEZ235; BLK, blank control; GEF, gefitinib.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4321659&req=5

f3-ott-8-269: H1975 cells were implanted into nude mice. (A) The tumor volume did not show significant difference, before treatment with different components. (B) The tumor volumes started to show differences with different components’ treatment. (C) The observation of tumors after 2 weeks of different components’ treatment.Abbreviations: B+G, NVP-BEZ235 combination with gefitinib; BEZ, NVP-BEZ235; BLK, blank control; GEF, gefitinib.
Mentions: In view of the in vitro growth-inhibiting effects of BEZ235 on H1975 cells, we verified its in vivo inhibitory action in nude mice. The mice were randomized into four groups with similar average tumor volume (Figure 3A). As expected, the tumor volume was decreased two weeks after BEZ235 administration. At the end of treatment, the average tumor volume of the blank group was 1973.22±156.04 mm3, while the average tumor volume of BEZ235 group was 1198.76±123.28 mm3 and 379.92±54.74 mm3 for the combination group, respectively. The tumor volumes of BEZ235 alone and the combination groups were significantly different from that of the blank group (P<0.05). These in vivo findings further demonstrated that BEZ235 significantly inhibited the growth of H1975 xenografts (Figure 3B and C).

Bottom Line: We show that NVP-BEZ235 effectively inhibited the growth of H1975 cells in vivo as well as in vitro.Similarly, H1975 cell migration was reduced by NVP-BEZ235.Taken together, we suggest that NVP-BEZ235 inhibits gefitinib-resistant tumor growth by downregulating PI3K/AKT/mTOR phosphorylation.

View Article: PubMed Central - PubMed

Affiliation: Oncology department, Xiangyang central Hospital, Xiangyang, Hubei, People's Republic of China.

ABSTRACT

Background: Patients harboring activating mutations in epidermal growth factor receptors (EGFR) are particularly sensitive to EGFR tyrosine kinase inhibitors (TKIs). However, most patients develop an acquired resistance after a period of about 10 months. This study focuses on the therapeutic effect of NVP-BEZ235, a dual inhibitor of phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR), in gefitinib-resistant non-small cell lung cancer.

Methods: H1975 cell line was validated as a gefitinib-resistant cell model by the nucleotide-sequence analysis. We used the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to detect the growth of H1975 cell line in vitro. H1975 cells' migration was detected by the migration assay. Xenograft models were used to investigate the growth of gefitinib-resistant non-small cell lung cancer in vivo. Western blot and immunohistochemical analysis were used to investigate the level of PI3K/protein kinase B(AKT)/mTOR signaling pathway proteins.

Results: We show that NVP-BEZ235 effectively inhibited the growth of H1975 cells in vivo as well as in vitro. Similarly, H1975 cell migration was reduced by NVP-BEZ235. Further experiments revealed that NVP-BEZ235 attenuated the phosphorylation of PI3K/AKT/mTOR signaling pathway proteins.

Conclusion: Taken together, we suggest that NVP-BEZ235 inhibits gefitinib-resistant tumor growth by downregulating PI3K/AKT/mTOR phosphorylation.

No MeSH data available.


Related in: MedlinePlus